The focus of this paper is to use our knowledge regarding pediatric subjects as a sensitive population to guide the discussion of three fundamental questions: (1) What scientific issues need to be considered in defining and characterizing a sensitive subpopulation? (2) What scientific data gaps exist in the procedures and approaches for assessing risk in sensitive populations? and (3) How well can existing procedures and approaches for assessing risk in the pediatric population as a sensitive subpopulation be extrapolated to other population groups?
The major scientific factors relating to pediatric sensitivity have been categorized into five groupings: physiological and behavioral parameters, pharmacokinetics, pharmacodynamics, genetics, and exposure. As a general statement, in all five categories used to characterize the pediatric population, lack of baseline data (as a function of life stage) on physiological processes, constitutive activity of key metabolic enzymes, DNA repair capacity and fidelity, gene expression and protein characterization, and behaviors related to exposure reduce the ability to qualitatively and quantitatively predict differences in sensitivity. In addition, lack of these same data also makes it difficult to interpret and quantify genetic, cultural, and environmental factors that alter baseline response and increase vulnerability. While acknowledging these limitations in each category, there are also lessons to be learned that translate to a broader description of what approaches could be used to identify and characterize other sensitive populations. In the following discussion, each category is evaluated for the three key questions that served as the impetus for this investigation.
There are lessons extracted from the pediatric population that inform the implications of physiological and kinetic differences between pediatric subjects and other life stages. This has been demonstrated through direct measurement of physiologic and metabolic capacity, adverse reactions to drugs due to modified phase 1 and phase 2 metabolism, and, in the laboratory, age-dependent differences in physiological capacities and enzyme content within human tissues and differences between adult-only exposed and fetal/perinatally exposed animals in toxic response for a variety of chemicals.
To characterize the potential differences in risk between subgroups of the general population, it is important to understand how these populations differ in the ontogeny of metabolizing enzymes in key metabolizing organs, as well as the rate of metabolism for each of the enzymes likely to alter a chemical in the body. This is not an easy task. First, defining the “average” response from which to develop baseline information between groups is problematic because metabolic capacity can be altered by genetic and cultural differences, as well as concomitant exposures (e.g., drugs) that can impact pharmacokinetics and pharmacodynamics through multiple mechanisms. The genetic differences between individuals can lead to complicated differences in metabolism depending upon whether that genetic difference is in the promoter region of a gene or in the transcribed region (Portier and Bell, 1998
). The cultural influences on metabolism arise through differences in diets and other exposures that can serve to inhibit, induce, or compete for key enzymatic activity, and these would need to be quantified in each population.
Given these observations, it is reasonable to presume that in the absence of scientific data, the pediatric and other subpopulations could be differentially sensitive to any drug or chemical. This presumption has led to the development of scientific databases that guide the evaluation of risks to the pediatric population for given exposures, and in the absence of that data, suggest default approaches that appropriately protect this population. By extrapolation, such scientific databases to guide evaluation of risk to other populations would be equally helpful. In addition, physiologically based pharmacokinetic models are seeing increased use in risk modeling and assessment, and the lessons learned from the kinetic differences observed in the pediatric population can and are being applied to other potentially sensitive populations. Filling in the knowledge gaps enumerated above will improve this process.
Pharmacodynamic susceptibilities seen in the pediatric population derive predominantly from the fact that their bodies are still in a developmental state with a different physiology from adults (e.g., higher breathing rates), higher cellular replication rates, ongoing tissue organization, and highly specialized cellular differentiation occurring only during development. Combining these processes with certain environmental insults that interact with them leads to the potential for sensitivity. Key among these processes are those governing DNA fidelity, gene expression and transcription, developmental differentiation (e.g., processes governing maturation of the immune system, processes governing apoptosis during development), and cellular migration. For all these processes, there are parallels in adults that can be informed by what we know from studies in the pediatric population. In addition, there can be long-term consequences of pharmacodynamic changes during development that create lifetime susceptibilities that can also be used to inform risk assessments.
There are genetic polymorphisms that result in increased risk of disease. In addition, there are genetic polymorphisms that, when linked with environmental exposures, alter disease risk from the exposure. These gene-environment interactions can affect both pediatric and adult subjects, but children may exhibit differential sensitivity relative to adults for a given gene-environment interaction based on expression levels of the gene product in question. Much of the knowledge available on genetic polymorphisms, environmental exposure, and disease in humans has focused on polymorphisms of key metabolizing enzymes for which the polymorphism results in altered metabolism of a xenobiotic resulting in a change in risk from exposure. The greatest focus in this area for the pediatric population has been in the area of genetic polymorphisms that alter the susceptibility of pediatric patients to the environmental triggers that initiate asthma attacks.
Information on the alteration of risks in the pediatric population from gene-environment interactions is limited. The majority of data in this area have been generated in adults and have focused on key metabolism genes. Hence, in this case, extrapolation from the adult to the pediatric subject is required, but can be problematic. However, with good baseline data, it should be possible to make a reasonable scientific judgment of the magnitude of the pediatric risk relative to the adult based on changes in the activity of the enzyme. Data quantifying such changes are becoming increasingly available. The implications for pediatric disease could be very different for a given genetic polymorphism and exposure due to differential expression of genes in different organs in the developing human as compared to the adult.
Lastly, pediatric behaviors and environments are different than those of adults. Given detailed models of pediatric and adult behaviors that allow for accurate exposure analyses, it is possible to more fully understand the exposure-driven differences in sensitivity between populations, by using their individual susceptibility linked to the detailed exposure analyses. Scientifically, the challenges here are in evaluating the behavior patterns, which can be quite varied and may be modified by a large number of additional factors such as socioeconomic status. In addition, the predominant route of exposure may be different for pediatric subjects versus adults, leading to differential sensitivities in organs and tissues.
Geographical, cultural, ethnic, and economic factors are all likely to play a role in behavior and in environmental exposures. Because these behaviors also are linked with age and because the vulnerability is also likely to change with age, understanding this interaction is key to determining vulnerability. Finally, as noted earlier, because the actual routes of exposure could change with life stage, a better understanding of the risks from exposures to environmental agents through different routes is needed, as are tools that will allow for extrapolations from one route to another in a life-stage–dependent manner.
In summary, this review of approaches and methods for assessing risk to the pediatric population has outlined a number of general issues pertaining to the identification and evaluation of vulnerable human populations. Below are key points:
- The pediatric population has been studied from a number of scientific perspectives relative to their potential vulnerability to environmental exposures, and this knowledge should be considered when evaluating potential vulnerability of other age groups and populations.
- Windows of sensitivity exist within the pediatric population that are defined by transient differences in pharmacokinetics, pharmacodynamics, physiology, behavior, and/or exposure. Transient differences in these same parameters may be useful in defining windows of sensitivity in other populations. Knowing the MOA of a given toxicant can help define a window of susceptibility for different life stages.
- Determination of sensitivity to any age group or population is dependent on multiple factors including genetic influences, pharmacokinetics and pharmacodynamics, behavior, exposure, and internal dosimetry. Collectively, these key determinants, and perhaps others yet to be defined, should be considered when evaluating potential vulnerability and impact on health risk.
- The MOA of many neurotoxicants appears to be highly dependent on specific properties of the developing nervous system. The extrapolation of these data to assist in the definition and characterization of other sensitive populations will require more knowledge about MOA and the specifics of developmental susceptibilities of the nervous system.
- The developing immune system is more susceptible and more sensitive to the effects of immunotoxicants, and adverse effects of toxicant exposure are often more persistent than in the mature immune system. Better understanding of the greater susceptibility of the developing organism may enhance the ability to predict adverse effects in susceptible subpopulations of adults with risk factors for decreased immunocompetence (e.g., advanced age, pregnancy, therapeutic and recreational drug use, stress).
- The pediatric population may be more susceptible to the mutagenic effects of oncogenic exposures, and this differential susceptibility could result in different effect levels at different exposures. Furthermore, pediatric cancers and their cures can make this population group susceptible to other exposures and increase disease risk (including for second cancers) in adulthood.
- The integration of life-stage–dependent pharmacokinetic and pharmacodynamic data into computational models has improved the utility of these tools for risk assessment. Similar knowledge regarding other potentially sensitive populations should be of equal value and improve our ability to assess risk for these subpopulations.